Mitochondrial DNA variants associated with metabolic syndrome

Abstract

Provided are methods of identifying Metabolic Syndrome phenotypes for an organism or a biological sample derived therefrom which methods are based on detecting a polymorphism, haplotype, haplotype group, or haplotype subgroup in the mitochondrial genome of the organism and correlating the polymorphism or haplotype to a Metabolic Syndrome phenotype. Also provided are systems or kits for the detection of such polymorphisms or haplotypes and the correlation of the polymorphisms or haplotypes to a Metabolic Syndrome phenotype. Provided are methods of identifying a modulator of a Metabolic Syndrome phenotype and kits for the treatment of a Metabolic Syndrome phenotype.

1 . A method of identifying a metabolic syndrome phenotype for an organism or biological sample derived therefrom, the method comprising:
 detecting, in the organism or biological sample, a polymorphism, haplotype, haplotype subgroup or haplotype group in a mitochondrial genome of the organism; and,   correlating the polymorphism or haplotype to the metabolic syndrome phenotype.   
     
     
         2 . A method of identifying a metabolic syndrome phenotype for an organism or biological sample derived therefrom, the method comprising:
 detecting, in the organism or biological sample, a polymorphism, haplotype, haplotype subgroup or haplotype group noted in the tables herein, wherein the polymorphism, haplotype, haplotype subgroup or haplotype group is associated with the metabolic syndrome phenotype; and,   correlating the polymorphism, haplotype, haplotype subgroup or haplotype group to the metabolic syndrome phenotype.   
     
     
         3 . The method of  claim 1  or  2 , wherein the correlation between a metabolic syndrome phenotype and a haplotype or haplotype subgroup comprises one or more of: E and waist circumference; F3 and waist circumference; F4 and increased risk for obesity, waist circumference and body mass index (BMI); M10 and decreased levels of triglycerides and systolic and diastolic blood pressure (SBP, DBP); N9a and decreased risk for type 2 diabetes (T2DM), cholesterol, and high density lipoprotein levels (HDL) in men; R9 and overall metabolic syndrome (MS); D and increased SBP; D5 and elevated cholesterol and SBP in women but decreased BMI for men; and D4b for very low triglycerides. 
     
     
         4 . The method of  claim 1  or  2 , wherein the organism is a human patient, or the biological sample is derived from a human patient. 
     
     
         5 . The method of  claim 1  or  2 , wherein the detecting comprises amplifying the polymorphism or a sequence associated therewith and detecting the resulting amplicon. 
     
     
         6 . The method of  claim 5 , wherein the amplicon is detected by a process that includes one or more of: hybridizing the amplicon to an array, digesting the amplicon with a restriction enzyme, or real-time PCR analysis. 
     
     
         7 . The method of  claim 5 , comprising partially or fully sequencing the amplicon. 
     
     
         8 . The method of  claim 5 , wherein the amplifying comprises performing a polymerase chain reaction (PCR), reverse transcriptase PCR (RT-PCR), or ligase chain reaction (LCR) using nucleic acid isolated from the organism or biological sample as a template in the PCR, RT-PCR, or LCR. 
     
     
         9 . The method of  claim 1  or  2 , wherein correlating the polymorphism comprises referencing a look up table that comprises correlations between alleles of the polymorphism and the phenotype. 
     
     
         10 . A system or kit comprising:
 an amplification composition or set of amplification reagents comprising one or more amplification primers that flank or comprise one or more polymorphisms that distinguish one or more haplotypes, haplotype subgroup or haplotype groups selected from: E, F3, F4, M10, N9a, R9, D, D5 and D4b; and,   a look up table that correlates one or more of the haplotypes, haplotype subgroups or haplotype groups to one or more metabolic syndrome phenotype.   
     
     
         11 . The system or kit of  claim 10 , comprising one or more containers that contain the amplification composition or amplification primers. 
     
     
         12 . The system or kit of  claim 10 , comprising computer-implemented instructions that correlate a product of the amplification composition or reagents with the metabolic syndrome phenotype using the look up table. 
     
     
         13 . A method of identifying a modulator of a metabolic syndrome phenotype, the method comprising:
 contacting a potential modulator to a gene or gene product, wherein the gene or gene product comprises a polymorphism within, or is at least partially encoded within a haplotype selected from: E, F3, F4, M10, N9a, R9, D, D5 and D4b; and,   detecting an effect of the potential modulator on the gene or gene product, thereby identifying whether the potential modulator modulates the metabolic syndrome phenotype.   
     
     
         14 . The method of  claim 13 , wherein the metabolic syndrome phenotype comprises insulin resistance, a lipid disorder, or central obesity. 
     
     
         15 . The method of  claim 13 , wherein the effect comprises increased or decreased expression of a gene encoding or corresponding to a polymorphism or haplotype herein in the presence of the modulator. 
     
     
         16 . A kit for treatment of a metabolic syndrome phenotype, the kit comprising a modulator identified by the method of  claim 13  and instructions for administering the compound to a patient to treat the metabolic syndrome phenotype. 
     
     
         17 . The kit of  claim 16 , wherein the metabolic syndrome phenotype is an obesity predisposition, dyslipidemia, or an insulin resistance phenotype.